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Stojkovska I, Wani WY, Zunke F, et al. Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking. Neuron. 2021;doi: 10.1016/j.neuron.2021.10.032.
Stojkovska, I., Wani, W. Y., Zunke, F., Belur, N. R., Pavlenko, E. A., Mwenda, N., Sharma, K., Francelle, L., & Mazzulli, J. R. (2021). Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking. Neuron, . https://doi.org/10.1016/j.neuron.2021.10.032
Stojkovska, Iva, et al. "Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking." Neuron vol. (2021). doi: https://doi.org/10.1016/j.neuron.2021.10.032
Stojkovska I, Wani WY, Zunke F, Belur NR, Pavlenko EA, Mwenda N, Sharma K, Francelle L, Mazzulli JR. Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking. Neuron. 2021 Nov 09; doi: 10.1016/j.neuron.2021.10.032. Epub 2021 Nov 09. PMID: 34793693.
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Neuron. 2021 Nov 09; doi: 10.1016/j.neuron.2021.10.032. Epub 2021 Nov 09.

Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking.

Neuron

Iva Stojkovska, Willayat Y Wani, Friederike Zunke, Nandkishore R Belur, Egor A Pavlenko, Nkatha Mwenda, Karan Sharma, Laetitia Francelle, Joseph R Mazzulli

Affiliations

  1. The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
  2. The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Molecular Neurology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
  3. The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: [email protected].

PMID: 34793693 DOI: 10.1016/j.neuron.2021.10.032

Abstract

Neurodegenerative disorders are characterized by a collapse in proteostasis, as shown by the accumulation of insoluble protein aggregates in the brain. Proteostasis involves a balance of protein synthesis, folding, trafficking, and degradation, but how aggregates perturb these pathways is unknown. Using Parkinson's disease (PD) patient midbrain cultures, we find that aggregated α-synuclein induces endoplasmic reticulum (ER) fragmentation and compromises ER protein folding capacity, leading to misfolding and aggregation of immature lysosomal β-glucocerebrosidase. Despite this, PD neurons fail to initiate the unfolded protein response, indicating perturbations in sensing or transducing protein misfolding signals in the ER. Small molecule enhancement of ER proteostasis machinery promotes β-glucocerebrosidase solubility, while simultaneous enhancement of trafficking improves ER morphology, lysosomal function, and reduces α-synuclein. Our studies suggest that aggregated α-synuclein perturbs the ability of neurons to respond to misfolded proteins in the ER, and that synergistic enhancement of multiple proteostasis branches may provide therapeutic benefit in PD.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: ER stress; Parkinson's disease; alpha-synuclein; beta-glucocerebrosidase; iPSC-derived midbrain dopaminergic neurons; lysosomal dysfunction; protein aggregation

Conflict of interest statement

Declaration of interests J.R.M. is a scientific co-founder of Lysosomal Therapeutics.

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